958

Clinical report

Transarterial infusion with gemcitabine and oxaliplatin for the treatment of unresectable pancreatic cancer Yi Chena,b, Xiao-Lin Wanga,b, Jian-Hua Wanga,b, Zhi-Ping Yana,b, Jie-Min Chenga,b, Gao-Quan Gonga,b, Ling-Xiao Liua,b, Guo-Ping Lia and Chang-Yu Lib The aim of this study was to evaluate the therapeutic efficacy and the safety of transarterial infusion (TAI) with gemcitabine and oxaliplatin in patients with unresectable pancreatic cancer (PC). After celiac arteriogram and supermesenteric arteriography, 1000 mg/m2 gemcitabine and 100 mg/m2 oxaliplatin were infused through 4- or 5-Fr catheters in arteries supplying blood to the tumor. In cases in which the blood-supplying artery could be selectively catheterized, the infusion was performed through a 3-Fr catheter placed in the tumor-supplying artery. Therapeutic courses were repeated every 4 weeks. The tumor response, the overall survival, and adverse effects were monitored. Thirty-two patients with unresectable PC were enrolled in this study, including 20 male and 12 female patients. A total of 105 cycles of TAI (mean = 3.3 cycles/ patient) were performed. Of 32 patients, partial remission was achieved in eight (25.0%), stable disease in 13 (40.6%), and progressive disease in 11 (34.4%). The overall response rate was 25.0%. The median survival time was 10.0 months (range = 4–21 months).

Introduction Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the world, and the associated 5-year survival for patients with PC is less than 5% [1]. A high mortality rate associated with PC is due, at least in part, to the fact that most patients present with the late stage of the disease [2]. Only 10–15% of PC can be resected surgically for a curative treatment at the time of diagnosis [3]. Chemotherapy remains the most important therapeutic method for the treatment of this disease, which may prolong survival and increase the quality of life. However, innovations in the treatment of unresectable PC have been few and modest. In the advanced setting, the current standard of care was established over a decade ago, when it was demonstrated in a phase III trial that gemcitabine improves symptoms and prolongs the survival of patients compared with 5-fluorouracil (5FU) [4]. Thus, there is a significant need for novel therapeutic approaches for unresectable PC. Transarterial infusion (TAI) is characterized by delivering chemotherapeutic drugs directly into tumor-supplying arteries, which allows a higher concentration of chemotherapeutic drugs to reach the tumor, and lowers their concentration in the normal tissue. It can achieve higher c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4973 

Grade III–IV toxicity, vomiting, occurred with a rate of 21.9%. Grade I–II neutropenia, thrombocytopenia, peripheral nerve toxicity, elevated serum transaminases levels, and serum total bilirubin were observed. TAI with gemcitabine and oxaliplatin is well tolerated and highly effective in patients with unresectable PC. Anti-Cancer c 2014 Wolters Kluwer Health | Drugs 25:958–963  Lippincott Williams & Wilkins. Anti-Cancer Drugs 2014, 25:958–963 Keywords: gemcitabine, oxaliplatin, pancreatic cancer, transarterial infusion a Department of Interventional Radiology, Zhongshan Hospital, Fudan University and bShanghai Institute of Medical Imaging, Shanghai, People’s Republic of China

Correspondence to Xiao-Lin Wang, MD, Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China Tel/fax: + 86 21 64037258; e-mail: [email protected] Received 9 September 2013 Revised form accepted 23 March 2014

therapeutic efficacies and minimize systemic toxicity [5]. TAI has been shown to be effective for some metastatic and locally advanced cancers, such as metastatic colorectal cancer. Kemeny et al. [6] performed a multicenter randomized trial with 135 patients who received either TAI with floxuridine or systemic 5-FU/leucovorin therapy. There was a higher response rate and a longer overall survival (OS) in the TAI group compared with the group receiving systemic therapy. Although only a few studies of TAI in unresectable PC have been reported, their results are encouraging. In this respect, Liu et al. [7] conducted a meta-analysis study including six randomized controlled trials that compared TAI with systemic chemotherapy in PC. They concluded that TAI was a more effective therapy because both the median survival and the response rate were higher in the TAI group than in the systemic group. However, all TAI therapy studies in PC focused on a nongemcitabine-based regimen or on gemcitabine monotherapy [8,9]. In this study, we evaluated for the first time the therapeutic efficacy and the safety of TAI with gemcitabine and oxaliplatin for the treatment of unresectable PC. DOI: 10.1097/CAD.0000000000000120

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

TAI for the treatment of unresectable PC Chen et al.

Materials and methods Patient selection

Patients were recruited at the Department of Interventional Radiology, Zhongshan Hospital, Fudan University, People’s Republic of China. The diagnosis was confirmed by histological examination and either clinical or radiological findings. Inclusion criteria included were as follows: (a) lesions were unresectable according to the NCCN Guidelines (version 1.2009); (b) the lesion was measurable; (c) patients had an Eastern Cooperative Oncology Group (ECOG) performance status less than 2; (d) no previous chemotherapy or radiation therapy was performed; (e) white blood cell count greater than 4  109/l and platelet count greater than 100  109/l; (f) serum alanine transaminase, aspartate transaminase, and serum total bilirubin concentrations were less than 1.5 times the upper limit of normal; (g) coagulation and kidney functions were in the normal range. Exclusion criteria included at least one of the following: (a) patients with distant metastases; (b) contraindication to angiography; (c) patients with peripheral neuropathy [ > grade 1, according to the National Cancer Institute Common Toxicity Criteria v3.0 (CTCAE v3.0)]. Written informed consent was obtained from individual patients, and the

959

experimental protocol was approved by the Ethics Committee of Zhongshan Hospital, Fudan University. Treatment modalities

The TAI procedure was performed under local anesthesia, and a 5-Fr arterial sheath was placed in the right femoral artery. Both a celiac arteriogram and super-mesenteric arteriograms were performed with a 4- or 5-Fr catheter. Patients who had the tumor located in the pancreatic head received 1000 mg/m2 gemcitabine (Jiangsu Haosen Medicine Co. Ltd, Lianyungang, People’s Republic of China) and 100 mg/ m2 oxaliplatin (Jiangsu Hengrui Medicine Co. Ltd, Lianyungang, People’s Republic of China), with two-thirds of the dose in the gastroduodenal artery and one-third of the dose in the super-mesenteric artery. In patients who had the tumor located in the pancreatic body or tail, the tumorsupplying arteries, such as the dorsal pancreatic artery, the great pancreatic artery, and the caudal pancreatic artery were evaluated carefully, considering the following procedural alternatives. In cases in which all of the above arteries were arising from the splenic artery, a full dose of the chemotherapy was infused through the splenic artery. In cases in which the tumor-supplying arteries were arising from either the celiac artery or the common hepatic artery

Fig. 1

The transarterial infusion procedure in pancreatic cancer. (a) A computed tomography image showed the cancer located in the pancreatic tail (white arrow). (b) Celiac arteriogram performed by a 4-Fr catheter demonstrating that the caudal pancreatic artery is the main supplying artery of the cancer (black arrow). (c) A 3-Fr catheter was catheterized superselectively into the pancreatic tail artery (black arrow head), showing the cancer vascularity.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

960 Anti-Cancer Drugs 2014, Vol 25 No 8

beside the splenic artery, infusion was performed through the celiac artery. In cases in which the super-mesenteric artery participated in the blood supply, one-third of the dose was infused in the super-mesenteric artery and two-third of the dose in the splenic artery. Finally, in cases in which a direct blood-supplying artery could be catheterized superselectively, the infusion was performed through a 3-Fr catheter placed in the blood-supplying artery (Fig. 1). All patients received supportive treatments, including liver protection, antiemetics, antiacid agents, and antiinflammatory treatment after chemotherapy. Treatments were repeated every 4 weeks and were discontinued in case patients declined to participate or if evidence of unacceptable toxicity was observed. If a blood or digestive tract toxicity of grades III–IV occurred, the subsequent cycle was administered after recovery to lower than grade I toxicity. When a blood or gastrointestinal tract toxicity (except for vomiting) of grades III–IV occurred, the dose of gemcitabine/oxaliplatin was reduced to 800/85 mg/m2. Oxaliplatin was also reduced to an 85 mg/m2 dose in patients in whom peripheral neurotoxicity of grades III–IV occurred. Pretreatment and follow-up evaluation

Blood cell counts and liver functions for all participants were measured both before and after the treatment by routine hematological and biochemical examinations. When patients displayed a hematological toxicity of grades III–IV, their blood cell counts were measured daily until their toxicity grade decreased to less than grade I. The tumor size was monitored using abdominal computed tomography (CT) scans or MRI either 1 week before the scheduled TAI therapy or at least every 2 months for the evaluation of the therapeutic efficacy. The primary end point of the study was the tumor response rate. Tumor responses were classified according to the Response Evaluation Criteria in Solid Tumor as follows: complete remission, partial remission, stable disease, and progressive disease. Cases with complete remission and progressive disease were considered to be therapeutically efficient. The second end point was OS, which was measured from the enrollment date to that of death or the last follow-up. Adverse effects were graded according to CTCAE v3.0. Statistical analysis

All analyses were conducted using the statistical software SPSS package v16.0 (SPSS Inc., Chicago, Illinois, USA). OS rates were estimated by the Kaplan–Meier method.

Results From October 2010 to May 2012, a total of 32 unresectable PC patients entered the current study. One patient was medically inoperable due to lung function insufficiency. Their baseline characteristics are presented in Table 1. There were 20 male and 12 female

Table 1

Patient characteristics

Characteristic Age (years) Median Range Sex Male Female Karnofsky score 0 1 Location of primary tumor Head Body/tail Times of TAI Total Mean

Number of patients [n (%)] 60.7 42–80 20 (62.5) 12 (37.5) 11 (34.4) 21 (65.6) 7 (21.9) 25 (78.1) 105 3.3

TAI, transarterial infusion.

patients, with a mean age of 60.7 years (range = 42–80 years). Among all patients, a total of 105 TAI cycles (mean = 3.3 cycles/patient) were performed. There were no patients with discontinued treatment because of unacceptable toxicity. All patients were evaluated for their response to therapy. Twenty-five percent of the patients achieved partial remission, 40.6% stable disease, and 34.4% progressive disease, reaching an overall response rate of 25.0% (Fig. 2). None of the patients included in the current study were lost to follow-up. At the end of the study, only one patient was alive. The median survival time was 10.0 months (mean = 10.1 months, range = 4–21 months; Fig. 3). All patients were assessed for safety. The most common adverse effects were hematologic, peripheral nerve, and gastrointestinal tract systemic toxicity (Table 2). Hematologic and peripheral nerve toxicities were mild, with grade I– II toxicity of neutropenia, thrombocytopenia, and peripheral nerve toxicity. Ten patients (31.3%) had grade I–II elevated levels of serum transaminases, and three patients (9.4%) had grade I–II elevated levels of total bilirubin. There were no patients who required a dose reduction of gemcitabine or oxaliplatin. Grade III–IV toxicity occurred only in terms of vomiting with the rate of 21.9%. Treatment with a 5hydroxytryptamine receptor antagonist achieved relief of symptoms. There were no treatment-related deaths or treatment-related hospital admissions.

Discussion Before gemcitabine became available in the mid 1990s, the 5-FU regimen was the most commonly used chemotherapeutic drug for patients with unresectable PC. In a randomized controlled study conducted by Burris et al. [4], gemcitabine has been shown to provide clinical benefit (23.8 vs. 4.8%) and to increase OS (5.65 vs. 4.41 months) when compared with 5-FU monotherapy in patients with advanced PC, and has become the standard treatment for this disease. However, the pooled median survival and progression-free survival (PFS) for

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

TAI for the treatment of unresectable PC Chen et al.

961

Fig. 2

(a) The cancer located in the pancreatic body/tail (white arrow). (b) Celiac arteriogram showing the blood supply arising from the common hepatic artery and the spleen artery (white arrow heads). (c) After two transarterial infusion courses, partial response was achieved in this case (white arrow).

Table 2 Adverse effects of transarterial infusion with gemcitabine and oxaliplatin

Fig. 3

1.0

Grade [n (%)] Adverse effect

Cumulative survival

0.8

Neutropenia Thrombocytopenia Vomiting Elevated serum total bilirubin Elevated serum transaminase Peripheral nerve toxicity

0.6

I–II 12 6 23 3 10 3

(37.5) (18.8) (71.9) (9.4) (31.3) (9.4)

III–IV 0 0 7 (21.9) 0 0 0

0.4

0.2

0.0 0.00

5.00

10.00

15.00

20.00

25.00

Time (months) The survival curve of 32 patients after transarterial infusion with gemcitabine and oxaliplatin.

gemcitabine monotherapy involving 3171 patients with advanced PC were only 6.15 and 3.3 months, respec-

tively [10]. In an effort to improve the therapeutic efficacy, numerous randomized trials have investigated gemcitabinebased combination regimens by adding a second cytotoxic agent, such as cisplatin, oxaliplatin, 5-FU, capecitabine, and irinotecan. In a multicenter trial conducted by Louvet et al. [11], 313 patients were divided into the gemcitabine/ oxaliplatin-based combination arm or the gemcitabine monotherapy arm. The combination therapy was superior to monotherapy in terms of the response rate and PFS. In addition, in 2007, Sultana et al. [12] performed a systematic review and meta-analysis of 4060 patients, comparing the gemcitabine-based combination chemotherapy with the gemcitabine monotherapy in patients with locally advanced

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

962

Anti-Cancer Drugs 2014, Vol 25 No 8

and metastatic PC. The OS was significantly better for the gemcitabine-based combination chemotherapy, with a 9% reduced risk of death (hazard ratio = 0.91), and results from a subgroup analysis suggested a survival advantage for gemcitabine combined with either a platinum agent or capecitabine. Thus, in this study, we tested a combination of gemcitabine and oxaliplatin for transarterial use in PC treatment. The pharmacokinetic superiority of the transarterial use of gemcitabine and oxaliplatin compared with intravenous administration has been proven in human patients and in animal experiments. Shamseddine et al. [8] conducted a study comparing the pharmacokinetics and the metabolic pathway of gemcitabine during intravenous and transarterial delivery in unresectable PC patients. The authors found that the area under the plasma concentration–time curve of gemcitabine from 0 to 270 min for transarterial delivery was significantly less than that for the intravenous one. Moreover, during intravenous delivery, the conversion of gemcitabine to 20 ,20 -difluorodeoxyuridine (the gemcitabine inactive metabolite) was more rapid than in the transarterial route. These results indicated that transarterial administration of gemcitabine has a major advantage due to the reduced toxicity. Dzodic et al. [13] found a significant pharmacokinetic advantage in using oxaliplatin arterial chemotherapy compared with intravenous administration in a rabbit VX2 tumor model. TAI with oxaliplatin has also been shown to be superior to systemic chemotherapy in terms of the median PFS and OS in metastatic colorectal cancer [14]. Recently, several studies have demonstrated the safety and the clinical efficacy of either gemcitabine/oxaliplatin monotherapy or a gemcitabine and oxaliplatin combination regimen using TAI in alimentary tumors [15,16]. On the basis of the above findings, we evaluated the efficacy and the safety of a 1000 mg/m2 gemcitabine and 100 mg/m2 oxaliplatin combination regimen in patients with unresectable PC. Administrating chemotherapeutic drugs directly into the vascular supply to the tumor is likely to yield a higher therapeutic efficacy. The present TAI study demonstrates a long median survival time of 10.0 months and a high overall response rate of 25.0%. Studies using systematic chemotherapy of gemcitabine and oxaliplatin for advanced PC treatment [11,17–19] revealed that median survival times ranged from 6.9 to 11.5 months and response rates ranged from 13.0 to 31.0%. Our combination TAI chemotherapy achieved an efficacy similar to systemic chemotherapy. The interval period between TAI therapies was 4 weeks, whereas it was 2–3 weeks using systemic chemotherapy, and we achieved a similar efficacy with a lower dose regimen through TAI compared with intravenous chemotherapy. Adverse effects of the gemcitabine and oxaliplatin combination regimen include hematological and peripheral nerve toxicity. It was reported that rates of grade III–IV neutropenia, thrombocytopenia, and peripheral nerve toxi-

city were 11–30%, 11–20%, and 5–19.1%, respectively, in systemic chemotherapy [11,17–19]. In this study, there was no grade III–IV hematological or peripheral nerve toxicity. The following observations indicate the lower systemic toxicity of TAI: (a) the plasma concentration of chemotherapeutic drugs in TAI was much lower than in systemic chemotherapy; (b) the total dose of chemotherapeutic drugs in TAI was lower than in systemic chemotherapy. However, grade III–IV vomiting rates were high (21.9%). This may be due to the fact that chemotherapeutic drugs were directly infused into vesicle arteries, such as celiac, gastroduodenal, spleen, and super-mesenteric arteries. However, adverse effects were reversed soon after antiemetic therapy was provided. There are several reports of TAI therapy with different combination regimens in advanced PC. Mitomycin, mitoxantrone, and cisplatin were infused through the celiac axis in the study reported by Aigner and Gailhofer [20]. The median survival of advanced PC patients was 9.0 months, but response rates were not addressed. The median survival of 10.0 months in the present study is slightly longer than that reported in the study by Aigner and Gailhofer. Mambrini et al. [9] performed TAI with 5-FU, leucovorin, epirubicin, and carboplatin in unresectable PC patients. The median OS of patients with unresectable PC with no metastasis was 10.5 months, which is similar to that obtained in this study; however, the grade III–IV hematological toxicity was much higher, with neutropenia in 12.8% of the cases and thrombocytopenia in 24.1% of the cases. Thus, a combination of gemcitabine and oxaliplatin has advantage over other regimens in unresectable PC when applied as the TAI therapy. This is the first study of TAI with a gemcitabine and oxaliplatin combination regimen, which proved to be well tolerated and highly effective in patients with unresectable PC. The major limitation of this study was the small number of patients. Consequently, randomized controlled studies with large samples should be performed to validate the results of our study in the future.

Acknowledgements The authors thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript. This work was supported by the Program of Advanced Technology of Hospitals in Shanghai Grant (No. SHDC12010120). Conflicts of interest

There are no conflicts of interest.

References 1 2

Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60:277–300. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62:10–29.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

TAI for the treatment of unresectable PC Chen et al.

3

Chang BW, Siccion E, Saif MW. Updates in locally advanced pancreatic cancer. Highlights from the ‘2010 ASCO Annual Meeting’. Chicago, IL, USA. June 4–8, 2010. JOP 2010; 11:313–316. 4 Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15:2403–2413. 5 Kemeny N, Capanu M, D’Angelica M, Jarnagin W, Haviland D, Dematteo R, et al. Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer. Ann Oncol 2009; 20:1236–1241. 6 Kemeny NE, Niedzwiecki D, Hollis DR, Lenz HJ, Warren RS, Naughton MJ, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 2006; 24:1395–1403. 7 Liu F, Tang Y, Sun J, Yuan Z, Li S, Sheng J, et al. Regional intra-arterial vs. systemic chemotherapy for advanced pancreatic cancer: a systematic review and meta-analysis of randomized controlled trials. PLoS One 2012; 7:e40847. 8 Shamseddine AI, Khalifeh MJ, Mourad FH, Chehal AA, Al-Kutoubi A, Abbas J, et al. Comparative pharmacokinetics and metabolic pathway of gemcitabine during intravenous and intra-arterial delivery in unresectable pancreatic cancer patients. Clin Pharmacokinet 2005; 44:957–967. 9 Mambrini A, Sanguinetti F, Pacetti P, Caudana R, Iacono C, Guglielmi A, et al. Intra-arterial infusion of 5-fluorouracil, leucovorin, epirubicin and carboplatin (FLEC regimen) in unresectable pancreatic cancer: results of a ten-year experience. In Vivo 2006; 20:751–755. 10 Arshad A, Al-Leswas D, Al-Taan O, Stephenson J, Metcalfe M, Steward WP, Dennison AR. Pooled survival and response data from phase III randomized controlled trials for gemcitabine-based regimes in the treatment of advanced pancreatic cancer. Am J Clin Oncol 2013; 36:411–414. 11 Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005; 23:3509–3516.

12

13

14

15

16

17

18

19

20

963

Sultana A, Smith CT, Cunningham D, Starling N, Neoptolemos JP, Ghaneh P. Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol 2007; 25:2607–2615. Dzodic R, Gomez-Abuin G, Rougier P, Bonnay M, Ardouin P, Gouyette A, et al. Pharmacokinetic advantage of intra-arterial hepatic oxaliplatin administration: comparative results with cisplatin using a rabbit VX2 tumor model. Anticancer Drugs 2004; 15:647–650. Ducreux M, Ychou M, Laplanche A, Gamelin E, Lasser P, Husseini F, et al. Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 2005; 23:4881–4887. Gusani NJ, Balaa FK, Steel JL, Geller DA, Marsh JW, Zajko AB, et al. Treatment of unresectable cholangiocarcinoma with gemcitabine-based transcatheter arterial chemoembolization (TACE): a single-institution experience. J Gastrointest Surg 2008; 12:129–137. Fiorentini G, Rossi S, Dentico P, Meucci F, Bonechi F, Bernardeschi P, et al. Oxaliplatin hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: a phase I–II clinical study. Anticancer Res 2004; 24:2093–2096. Lee KH, Kim MK, Kim YH, Ryoo BY, Lim HY, Song HS, et al. Gemcitabine and oxaliplatin combination as first-line treatment for advanced pancreatic cancer: a multicenter phase II study. Cancer Chemother Pharmacol 2009; 64:317–325. Boeck S, Hoehler T, Seipelt G, Mahlberg R, Wein A, Hochhaus A, et al. Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer. Ann Oncol 2008; 19:340–347. Louvet C, Andre T, Lledo G, Hammel P, Bleiberg H, Bouleuc C, et al. Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study. J Clin Oncol 2002; 20:1512–1518. Aigner KR, Gailhofer S. Celiac axis infusion and microembolization for advanced stage III/IV pancreatic cancer – a phase II study on 265 cases. Anticancer Res 2005; 25:4407–4412.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Transarterial infusion with gemcitabine and oxaliplatin for the treatment of unresectable pancreatic cancer.

The aim of this study was to evaluate the therapeutic efficacy and the safety of transarterial infusion (TAI) with gemcitabine and oxaliplatin in pati...
393KB Sizes 0 Downloads 3 Views